The renin-angiotensin system is one of the hormonal mechanisms involved in regulation of pressure/volume homeostasis and expression of hypertension. Activation of the renin-angiotensin cascade begins with renin secretion from the juxtaglomerular apparatus of the kidney and culminates in the formation of angiotensin II, the primary active species of this system. This octapeptide, angiotensin II, is primarily known as a very potent vasoconstrictor agent. It has a number of other effects which include promoting aldosterone secretion, direct effects on the kidney to promote sodium and fluid retention, feedback inhibition of renin secretion, increased sympathetic nervous system activity, increasing vasopressin secretion, causing positive cardiac inotropic effect and modulation of other hormonal systems. Angiotensin II is further degraded to the heptapeptide, angiotensin III {[des Asp.sup.1 ]angiotensin II} by non-specific aminopeptidases. Angiotensin III exhibits a wide range of potency in modulating biological responses upon binding to angiotensin II receptors. For example, angiotensin III is less potent as a vasoconstrictor than angiotensin II, but is similar to angiotensin II in stimulating aldosterone secretion.
A number of amino-, carboxy- and endopeptidases eventually degrade angiotensin III to inactive fragments. Previous studies have shown that antagonizing angiotensin II at its receptors is a viable approach to inhibit the renin-angiotensin system, given the pivotal role of this octapeptide which mediates the actions of the renin-angiotensin system through interaction with various tissue receptors. There are available angiotensin II antagonists most of which are peptidic in nature. Such peptidic compounds are of limited use due to their lack of oral bioavailablity and their short duration of action. Also, commercially available peptidic angiotensin II antagonists (e.g., Saralasin) have a significant residual agonist activity which further limit their therapeutical application.
Non-peptidic compounds with angiotensin II antagonist properties are known. For example, the sodium salt of 2-n-butyl-4-chloro-1-(2-chlorobenzyl) imidozole-s-acetic acid displayed specific competitive angiotensin II antagonist activity in a series of binding experiments, functional assays and in vivo tests [P. C. Wong et al, J. Pharmacol. Exp. Ther., 247, (1) 1-7 (1988)]. The sodium salt of 2-butyl-4-chloro-1-(2-nitrobenzyl)imiadzole-5-acetic acid has specific competitive angiotensin II antagonist activity as shown in a series of binding experiments, functional assays and in vivo test [A. T. Chiu et al, European J. Pharmacol., 157, 3121 (1988)]. A family of 1-benzylimidazole-5-acetate derivatives has been shown to have competitive angiotensin II antagonist properties, [A. T. Chiu et al., J. Pharmacol. Exp. Ther., 250 (3), 867-874]. U.S. Pat. No. 4,816,463 to Blankey et al. describes a family of 4,5,6,7-tetrahydro-1H-imidazo(4,5-C)-tetrahydro-pyridine derivatives useful as antihypertensives, some of which are reported to antagonize the binding of labelled angiotensin II to rat adrenal receptor preparation causing a significant decrease in mean arterial blood pressure in conscious hypertensive rats. E.P. No 253,310, published Jan. 20, 1988, describes a series of aralkyl imidazole compounds, including in particular a family of biphenyl substituted imidazoles, as antagonists to the angiotensin II receptor.
Several families of cycloheptimidazolone derivatives have been synthesized. For example, the synthesis of 1-benzyl-2-isopropyl-5,7-dimethylimidazo[4,5-d]cycloheptatrienon-6-one hydrochloride and 1-benzyl-2-isopropyl-5,7-dicarbethoxyimidazo[4,5-d]cycloheptatrienon-6-one which are characterized by N-1 and C-2 substituants limited to isopropyl and to benzyl, respectively [E. F. Godefroi et al, Receuil, 91, 1383-92, (1971)]. The compound 2-ethoxy-6(1H)-cycloheptimidazolone has been prepared [G. Senagawa et al, Chem. Pharm. Bull., 16, 1308-15, (1968)]. Synthesis of the compound 2-amino-1-methyl-6(1H)-cyclohepimidazolone has been reported [N. Tatsuo et al, Bull. Chem. Soc. Japan 35, 1188 (1962)]. None of these publications mentions any pharmaceutical use.
Several other cycloheptimidazolone derivatives with no substituents on the C-2 position have been reported. For example, a synthesis of a family of 5,7-symmetrically disubstituted-N-methylimidazo[4,5-d]cycloheptatrien-6-one has been reported, including specifically the compound 1,5,7-trimethyl-6(1H)-cycloheptimidazolone [M. El Borai et al., Egypt. J. Chem., 28, 139-44 (1985)]. Also the compound 1,6-dihydro-1-methyl-6-oxo-5,7-cycloimidazoledicarboxylic acid, its methyl and ethyl ester and 1-methyl-6(1H)-cycloheptimidazolone have been synthesized [M. El Borai et al., J. Prakt. Chem., 325, 853-856 (1983)]. Synthesis of the compound 5,7-diphenyl- and 5,7-dichloro-1-methyl-6(1H)-cycloheptimidazolone are also described [M. El Borai et al, OPPI BRIEFS, 14, 409-414 (1982)]. None of these compounds is substituted at the C-2 position. None of these publications mentions any pharmaceutical use.
Other types of cycloheptimidazoles are known. For example, Japanese Patent No. 43/26504 of Nov. 14, 1968 describes 2-phenyl-6(1H)-cycloheptimidazolone, 1-methyl-2-phenyl-6(1H)-cycloheptimidazolone and 1-p-tolyl-2-phenyl-6(1H)-cycloheptimidazolone. These compounds, which are characterized by an aryl group at position C-2 and the lack of substituants at positions C-5 and C-7, are for use as desensitizing agents in photographic processes. No mention is made of any pharmaceutical utility.
Japanese Patent No. 65/060069 of Jan. 27, 1970, describes certain cycloheptaimidazole derivatives having antiphlogistic activity.